Single-cell transcriptomics of blood reveals a nature killer cell subset depletion in tuberculosis. Homo sapiens

Background: Tuberculosis (TB) continues to be a critical global health problem, which killed millions of lives each year. Certain circulating cell subsets are thought to differentially modulate the host immune response towards Mycobacterium tuberculosis (Mtb) infection, but the nature and function of these subsets is unclear.Methods: We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMC) from healthy controls (HC), latent tuberculosis infection (LTBI) and active tuberculosis (TB).Findings: Cluster analysis based on differential gene expression revealed both known and novel markers for all main PBMC types and delineated 25 cell subsets. By comparing the scRNA-seq datasets from HC, LTBI and TB, we found that infection changes the frequency of immune-cell subsets during TB development. Specifically, we observed gradual depletion of a NK cell subset (CD3-CD7+GZMB+) from HC, to LTBI and TB. We further verified that the depletion of CD3-CD7+GZMB+ subset in TB and confirmed that changes in this subset frequency can distinguish patients with TB from LTBI and HC.Interpretation: We propose that the frequency of CD3-CD7+GZMB+ in peripheral blood could be used as a novel biomarker for distinguishing TB from LTBI and HC.

背景：结核病（Tuberculosis, TB）仍是严峻的全球公共卫生问题，每年造成数百万患者死亡。现有研究认为，部分循环细胞亚群可差异性调控宿主针对结核分枝杆菌（Mycobacterium tuberculosis, Mtb）感染的免疫应答，但此类亚群的本质与功能仍不明确。
方法：本研究对健康对照（healthy controls, HC）、潜伏结核感染（latent tuberculosis infection, LTBI）及活动性结核病（TB）受试者的外周血单个核细胞（peripheral blood mononuclear cells, PBMC）开展单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）。
结果：基于差异基因表达的聚类分析不仅鉴定出所有主要PBMC类型的已知及新型标志物，还明确划分出25个细胞亚群。通过对比HC、LTBI及TB受试者的scRNA-seq数据集，本研究发现感染在结核病进展过程中会改变免疫细胞亚群的占比。具体而言，我们观察到从HC到LTBI再到TB，自然杀伤细胞亚群（CD3-CD7+GZMB+）的比例呈渐进性减少。本研究进一步验证了结核病患者体内CD3-CD7+GZMB+亚群的耗竭现象，并证实该亚群的占比变化可有效区分结核病患者与LTBI及HC受试者。
解读：本研究提出，外周血中CD3-CD7+GZMB+亚群的占比可作为区分结核病与LTBI及HC受试者的新型生物标志物。